Bacterial Pathogenesis, Molecular Basis of
561
alginate production in
P. aeruginosa
(the
AlgZ/AlgR system).
In addition to the two-component sys-
tems, a number of other regulatory factor
families have been implicated in viru-
lence factor regulation. The families are
usually based on the homology or conser-
vation of distinct motifs (e.g. the ability
to bind a speciFc DNA element) within
the members of the group. Two of the
best-characterized are the AraC and LysR
regulator families. The AraC regulators are
a group of proteins that exhibit homologies
to the AraC protein, which regulates ara-
binose utilization in
E. coli
.Theseproteins
bind to speciFc DNA sequences upstream
of target genes to regulate their expres-
sion. A member of the AraC family, the
Vir± protein of
Yersinia spp
.isinvo
lvedin
regulating the expression of the Yop pro-
teins, which are involved in the virulence
of this organism. It should be noted that
the expression of Vir± itself is regulated
by temperature and that the Yop proteins
are only expressed at 37
C, demonstrat-
ing the networking of different regulatory
mechanisms to produce expression of the
correct product at the correct time during
infection. The LysR family includes SpvR,
a DNA-binding protein that regulates the
expression of a number of genes required
for the survival of
Salmonella spp
.inthe
mouse.
Over the past decade, a strong connec-
tion has been made between the coor-
dination of population density and the
regulation of virulence genes in a mech-
anism known as
quorum sensing
.T
h
i
s
coordination is achieved by the interac-
tion of small organic signal molecules,
which can traverse the bacterial cell wall,
with speciFc receptor proteins that can act
as regulators of transcription. In gram-
negative organisms, the signals appear to
be primarily homoserine lactones, while
gram-positive organisms appear to use
peptides. It is proposed that as cell popula-
tion density increases, the concentration
of the appropriate signal molecule in-
creases both external and internal to the
bacterial cell. Within the pathogen, the
number of regulator/signal complexes is
increased until, upon reaching a threshold
concentration, gene expression is coordi-
nated. The discovery of this mechanism
in pathogens is relevant to the observa-
tion that many pathogens must reach a
critical density within the host prior to
causation of disease. It is postulated that
quorum sensing is used by pathogens to
allow production of virulence factors at
theappropriatet
imeduringinfect
ionand
that the pathogen can unleash an arse-
nal of factors to overwhelm the host. As
an extension of this postulate, it may be
proposed that a pathogen does not express
unwanted factors too early, a situation that,
in addition to being wasteful, may also
give premature warning of the pathogen’s
presence to the immune system. The Feld
of quorum sensing is intensively studied,
and the list of pathogens that use such a
mechanismaswellasthevirulencefactors
regulated by this mechanism is rapidly
expanding.
5
The Pathogenic Cycle
In the previous section, there was a dis-
cussion of the steps that most pathogens
undertake in their progression to causing
disease. In the sections that follow, these
steps will be described to allow the reader
to gain some appreciation of the complex-
ity of the process as well as to gain some
insight into the hurdles that pathogens
face within the human host.
previous page 561 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 563 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off